1. Compulsive drug use is associated with imbalance of orbitofrontal- and prelimbic-striatal circuits in punishment-resistant individuals Substance use disorders (SUDs) impose severe negative impacts upon individuals, their families, and society. Clinical studies demonstrate that some chronic stimulant users are able to curtail their drug use when faced with adverse consequences while others continue to compulsively use drugs. The mechanisms underlying this dichotomy are poorly understood, which hampers the development of effective individualized treatments of a disorder that currently has no Food and Drug Administration-approved pharmacological treatments. In the present study, using a rat model of methamphetamine self-administration (SA) in the presence of concomitant foot shocks, thought to parallel compulsive drug taking by humans, we found that SA behavior correlated with alterations in the balance between an increased orbitofrontal cortex-dorsomedial striatal go circuit and a decreased prelimbic cortex-ventrolateral striatal stop circuit. Critically, this correlation was seen only in rats who continued to self-administer at a relatively high rate despite receiving foot shocks of increasing intensity. While the stop circuit functional connectivity became negative after repeated SA in all rats, shock-resistant rats showed strengthening of this negative connectivity after shock exposure. In contrast, shock-sensitive rats showed a return toward their baseline levels after shock exposure. These results may help guide novel noninvasive brain stimulation therapies aimed at restoring the physiological balance between stop and go circuits in SUDs. (Hu et a., PNAS, 2019) 2. Intrinsic Insular-Frontal Networks Predict Future Nicotine Dependence Severity Although 60% of the US population have tried smoking cigarettes, only 16% smoke regularly. Identifying this susceptible subset of the population before the onset of nicotine dependence may encourage targeted early interventions to prevent regular smoking and/or minimize severity. While prospective neuroimaging in human populations can be challenging, preclinical neuroimaging models before chronic nicotine administration can help to develop translational biomarkers of disease risk. Chronic, intermittent nicotine (0, 1.2, or 4.8 mg/kg/d; N = 10-11/group) was administered to male Sprague Dawley rats for 14 d; dependence severity was quantified using precipitated withdrawal behaviors collected before, during, and following forced nicotine abstinence. Resting-state fMRI functional connectivity (FC) before drug administration was subjected to a graph theory analytical framework to form a predictive model of subsequent individual differences in nicotine dependence. Whole-brain modularity analysis identified five modules in the rat brain. A metric of intermodule connectivity, participation coefficient, of an identified insular-frontal cortical module predicted subsequent dependence severity, independent of nicotine dose. To better spatially isolate this effect, this module was subjected to a secondary exploratory modularity analysis, which segregated it into three submodules (frontal-motor, insular, and sensory). Higher FC among these three submodules and three of the five originally identified modules (striatal, frontal-executive, and sensory association) also predicted dependence severity. These data suggest that predispositional, intrinsic differences in circuit strength between insular-frontal-based brain networks before drug exposure may identify those at highest risk for the development of nicotine dependence. (Hsu et al., J. Neuroscience, 2019) 3. Effects of age-related spatial memory decline on the anterior insular network of rats Spatial learning and memory are particularly vulnerable to age-related cognitive decline. Lesion studies in rodent models suggest that the anterior insula may play a role in spatial memory. In this study, using functional MRI on a cognitive aging model, we investigate the effects of aging and associated cognitive decline on the insula-centric network. 12 Young (6-9 months) and 24 aged (24-26 months) rats were tested on a Morris water maze task and underwent resting-state functional MRI scans. Aged rats were subsequently subdivided into aged unimpaired and impaired rats, based on their performance on the task quantified by a learning index (LI), while the aged unimpaired rats having similar LI as the young rats. Functional connectivity maps using anterior insula as a seed were generated for individual rats. A voxelwise one-way ANOVA and voxelwise regression with LI were conducted. The one-way ANOVA showed a significant group effect in anterior insular connectivity with frontal cortices, sensory cortices and hippocampus (corrected p < 0.05 with), in that the connectivity was lower in aged rats. The regression analysis exhibited that insular-hippocampal connectivity was correlated with LI (corrected p < 0.05), in that lower connectivity was accompanied by worse spatial memory performance, particularly in aged impaired rats. The reduced AI connectivity in aged rats and association of AI-hippocampus connectivity with spatial memory performance implicate disruption of AI network connectivity is related to cognitive decline in normal cognitive aging and suggest a pivotal role of the AI in neural reorganization in aging.